Dexophen

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEXOFEN (DEXOFEN)

Composition:

Active substance: dexketoprofen;

1 ml of injection solution contains dexketoprofen trometamol 36.91 mg, equivalent to dexketoprofen 25 mg (one 2 ml ampoule contains dexketoprofen trometamol 73.8 mg, equivalent to dexketoprofen 50 mg);

Excipients: sodium chloride; ethanol 96 %; sodium hydroxide; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution, free from mechanical inclusions.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and anti-rheumatic drugs. Propionic acid derivatives. Dexketoprofen. ATC code M01A E17.

Pharmacological Properties

Pharmacodynamics

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl) propionic acid, exerting analgesic, anti-inflammatory, and antipyretic effects, and belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of Action

The mechanism of action of NSAIDs is based on reducing prostaglandin synthesis by inhibiting cyclooxygenase activity. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. Additionally, inhibition of prostaglandin synthesis may affect other mediators of inflammation such as kinins, which may also indirectly influence the primary drug effect.

Pharmacodynamics

Inhibitory effects of dexketoprofen trometamol on the activity of both cyclooxygenase-1 and cyclooxygenase-2 have been demonstrated in laboratory animals and in humans.

Clinical Efficacy and Safety

Clinical studies in various types of pain have shown that dexketoprofen trometamol exerts pronounced analgesic effects. The analgesic effect of dexketoprofen trometamol following intramuscular or intravenous administration in patients with moderate to severe pain has been studied in various surgical procedures (orthopedic and gynecological surgeries, abdominal surgeries), as well as in musculoskeletal pain (acute low back pain) and renal colic. In these studies, the analgesic effect of the drug began rapidly and reached its maximum within 45 minutes.

The duration of analgesic effect after administration of 50 mg dexketoprofen trometamol typically lasts 8 hours. Clinical studies have demonstrated that using this drug allows a significant reduction in opioid dosage when used concomitantly for postoperative pain management. When patients receiving morphine via a patient-controlled analgesia device for postoperative pain were also given dexketoprofen trometamol, they required significantly less morphine (30–45% less) compared to patients receiving placebo.

Pharmacokinetics

Absorption

After intramuscular administration of dexketoprofen trometamol in humans, maximum concentration (Cmax) is reached approximately within 20 minutes (10–45 minutes). It has been demonstrated that following single intramuscular or intravenous administration of 25–50 mg of the drug, the area under the concentration–time curve (AUC) is proportional to the dose.

Distribution

Similar to other drugs with a high degree of plasma protein binding (99%), the volume of distribution of dexketoprofen averages 0.25 L/kg. The distribution half-life is approximately 0.35 hours, and the elimination half-life ranges from 1 to 2.7 hours.

Pharmacokinetic studies with repeated administration of the drug demonstrated that Cmax and AUC after the last intramuscular or intravenous dose did not differ from those after single administration, indicating absence of drug accumulation.

Biotransformation and Elimination

Metabolism of dexketoprofen occurs mainly via conjugation with glucuronic acid followed by renal excretion. After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in urine, indicating absence of in vivo conversion of the drug to the R-(-) optical isomer in humans.

Elderly Patients

Following administration of single and multiple doses, the extent of exposure in elderly healthy volunteers (aged 65 years and older) participating in the study was significantly higher (up to 55%) compared to younger volunteers; however, no statistically significant differences in maximum concentration (Cmax) or time to reach Cmax (tmax) were observed. The mean elimination half-life was prolonged (by up to 48%), and total systemic clearance was reduced.

Preclinical Safety Data

Standard preclinical studies—including pharmacological safety, genotoxicity, and immunopharmacology assessments—did not reveal any specific hazard for humans. Chronic toxicity studies in animals identified a no-observed-adverse-effect level (NOAEL) that was twice the recommended human dose. When higher doses were administered to monkeys, the main adverse reactions included fecal blood, reduced body weight gain, and, at the highest dose, gastrointestinal lesions such as erosions. These effects occurred at doses resulting in drug exposure 14 to 18 times higher than that observed at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may cause embryotoxicity or fetal death in animals, either directly by affecting embryonic or fetal development, or indirectly via adverse effects on the gastrointestinal tract of the mother.

Clinical characteristics.

Indications.

Symptomatic treatment of acute moderate to severe pain when oral administration of the drug is inappropriate, such as in postoperative pain, renal colic, and back pain.

Contraindications.

• Hypersensitivity to dexketoprofen, to any other NSAID, or to excipients of the drug;
• if substances with similar action, e.g. acetylsalicylic acid or other NSAIDs, provoke attacks of bronchial asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria, or angioedema;
• if photoallergic or phototoxic reactions occurred during treatment with ketoprofen or fibrates;
• gastrointestinal bleeding or perforation in medical history associated with previous NSAID therapy;
• patients with active peptic ulcer/gastrointestinal bleeding or with history of gastrointestinal bleeding, ulcers, or perforations;
• patients with chronic dyspepsia;
• active phase of other bleeding or increased bleeding tendency;
• Crohn’s disease or ulcerative colitis;
• severe heart failure;
• moderate or severe renal impairment (creatinine clearance ≤59 mL/min);
• severe hepatic impairment (10–15 points on the Child–Pugh scale);
• hemorrhagic diathesis and other coagulation disorders;
• pronounced dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy and breastfeeding period.

Due to the ethanol content in the medicinal product, the drug is contraindicated for neuroaxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other types of interactions.

Concomitant use of the following medicinal products with NSAIDs is not recommended:

• Other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g daily): concomitant use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to their mutually enhancing effects.
• Anticoagulants: NSAIDs enhance the effect of anticoagulants, e.g. warfarin, due to high plasma protein binding of dexketoprofen, as well as inhibition of platelet function and damage to gastric and duodenal mucosa. If concomitant use is necessary, it should be carried out under strict medical supervision with monitoring of appropriate laboratory parameters.
• Heparins: increased risk of bleeding (due to inhibition of platelet function and damage to gastric and duodenal mucosa); if concomitant use is necessary, it should be performed under strict medical supervision with monitoring of appropriate laboratory parameters.
• Corticosteroids: increased risk of gastrointestinal ulceration or gastrointestinal bleeding.
• Lithium (reports exist for several NSAIDs): NSAIDs increase lithium blood levels, potentially leading to toxicity (reduced renal excretion of lithium); therefore, lithium blood levels should be monitored at the start of dexketoprofen therapy, during dose adjustment, or upon discontinuation of the drug.
• High-dose methotrexate (≥ 15 mg weekly): due to reduced renal clearance of methotrexate under NSAID therapy, its negative effects on the blood system are generally enhanced.
• Hydantoin derivatives and sulfonamides: possible increased toxicity of these substances.

Concomitant use of the following medicinal products with NSAIDs requires caution:

• Diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists: dexketoprofen reduces the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydration or elderly patients), concomitant use of drugs that inhibit cyclooxygenase with ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may worsen renal function, which is usually reversible. When using dexketoprofen with any diuretic, ensure the patient is not dehydrated and monitor renal function at the beginning of treatment.
• Low-dose methotrexate (< 15 mg weekly): reduced renal clearance of methotrexate under NSAID therapy enhances its negative effects on the blood system. During the first weeks of concomitant use, weekly blood tests are required. Treatment should be conducted under strict medical supervision even in cases of mild renal impairment and in elderly patients.
• Pentoxifylline: risk of bleeding; enhanced monitoring and more frequent measurement of bleeding time are required.
• Zidovudine: risk of increased toxic effects on erythrocytes due to effects on reticulocytes, leading to severe anemia after one week of NSAID use; blood test and reticulocyte count should be performed within 1–2 weeks after starting NSAID therapy.
• Sulfonylurea drugs: NSAIDs may enhance the hypoglycemic effect of these drugs due to displacement of sulfonylureas from plasma protein binding sites.

Possible interactions should be considered when using the following medicinal products:

• β-blockers: NSAIDs may reduce their antihypertensive effect by inhibiting prostaglandin synthesis.
• Cyclosporine and tacrolimus: possible increased nephrotoxicity due to NSAID effects on renal prostaglandins; renal function should be monitored during combination therapy.
• Thrombolytic agents: increased risk of bleeding.
• Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding.
• Probenecid: possible increase in dexketoprofen plasma concentration, likely due to inhibition of renal tubular secretion and glucuronidation of the drug, requiring dose adjustment of dexketoprofen.
• Cardiac glycosides: NSAIDs may increase glycoside plasma concentrations.
• Mifepristone: theoretically, there is a risk of altered mifepristone efficacy under the influence of prostaglandin synthetase inhibitors. Limited data suggest that concomitant administration of NSAIDs on the same day as prostaglandin does not adversely affect the efficacy of mifepristone or prostaglandin regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of drugs for medical termination of pregnancy.
• Quinolone antibiotics: animal studies have shown that using quinolone derivatives in high doses in combination with NSAIDs increases the risk of seizures.
• Tenofovir: concomitant use with NSAIDs may increase plasma levels of blood urea nitrogen and creatinine; therefore, monitoring of renal function is required to assess the potential impact of concomitant use of these drugs.
• Deferasirox: concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity; careful patient monitoring is required when using this drug together with deferasirox.
• Pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, particular caution is required when using NSAIDs at high doses. Patients with mild to moderate renal impairment (creatinine clearance 45–79 mL/min) should avoid concomitant use of pemetrexed and NSAIDs for two days before and two days after pemetrexed administration.

Special precautions for use.

The drug should be used with caution in patients with a history of allergic conditions. Avoid concomitant use of the drug with other NSAIDs, including selective cyclooxygenase-2 inhibitors. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration, or perforation, in some cases fatal, have been observed during treatment with all NSAIDs at various stages of therapy, regardless of the presence of preceding symptoms or a history of serious gastrointestinal pathology. If gastrointestinal bleeding develops, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses in patients with a history of peptic ulcer, especially complicated by bleeding or perforation, as well as in elderly patients.

Elderly patients. Elderly patients have an increased frequency of NSAID-related adverse reactions, particularly gastrointestinal bleeding and perforation, sometimes fatal. Treatment in these patients should be initiated at the lowest possible dose. Before starting treatment with dexketoprofen trometamol in patients with a history of esophagitis, gastritis, and/or peptic ulcer, it should be ensured that these conditions are in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible gastrointestinal complications during treatment, particularly gastrointestinal bleeding. NSAIDs should be prescribed with caution in patients with a history of gastrointestinal disorders (ulcerative colitis, Crohn's disease), as there is a risk of exacerbation. NSAID use may trigger relapses of non-specific ulcerative colitis and Crohn's disease in patients in remission. For such patients and those taking low-dose acetylsalicylic acid or other drugs increasing the risk of gastrointestinal adverse reactions, combination therapy with gastroprotective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients, especially elderly ones, with a history of gastrointestinal adverse reactions should inform their physician about any unusual gastrointestinal symptoms, particularly gastrointestinal bleeding, especially during the initial stages of treatment.

The drug should be prescribed with caution to patients who are concurrently using medications that may increase the risk of ulceration or bleeding: oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid.

Renal function impairment

The drug should be used with caution in patients with impaired renal function, as NSAID use may lead to renal dysfunction, fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients receiving diuretics or those at risk of hypovolemia. During treatment, adequate fluid intake should be maintained to prevent dehydration, which may exacerbate renal toxicity. Like all NSAIDs, the drug may increase plasma urea nitrogen and creatinine concentrations. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic function impairment

The drug should be used with caution in patients with impaired liver function. As with other NSAIDs, the drug may cause transient and mild elevations in certain liver function parameters, as well as marked increases in AST and ALT activity. If such elevations occur, therapy should be discontinued.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety

Patients with arterial hypertension and/or mild to moderate heart failure require monitoring and medical supervision. Particular caution is required when treating patients with a history of cardiac disease, especially previous episodes of heart failure (the risk of heart failure increases during treatment), as fluid retention and edema may occur with NSAID therapy. Clinical studies and epidemiological data suggest that some NSAIDs (particularly at high doses and prolonged use) may slightly increase the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Data to exclude this risk with dexketoprofen use are insufficient. Therefore, dexketoprofen should be prescribed only after careful patient assessment in cases of uncontrolled arterial hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Similarly careful assessment is required before initiating long-term treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. The concomitant use of dexketoprofen trometamol and low-molecular-weight heparin at prophylactic doses in the postoperative period has been studied in clinical trials, with no effect on coagulation parameters observed. However, patients receiving dexketoprofen trometamol concurrently with drugs affecting hemostasis, such as warfarin, other coumarin derivatives, or heparin, require close medical supervision. Cardiovascular function disturbances occur most frequently in elderly patients.

Skin reactions

There have been reports of very rare cases of serious skin reactions (some fatal) associated with NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk likely occurs early in treatment, with most cases appearing within the first month of therapy. If skin rashes, signs of mucosal involvement, or other hypersensitivity symptoms occur, the drug should be discontinued.

Other information

Particular caution is required when prescribing the drug to patients:

• with inherited porphyrin metabolism disorders (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical procedures.

If prolonged use of dexketoprofen is deemed necessary by the physician, regular monitoring of liver and kidney function is recommended.

In very rare cases, severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If early signs of severe hypersensitivity reactions occur after drug administration, treatment should be discontinued. Depending on symptoms, any necessary treatment should be administered under medical supervision.

Patients suffering from asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs compared to other patients. Use of this drug may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

Severe infectious complications involving the skin and soft tissues may occur during varicella. Data to exclude a role of NSAIDs in exacerbating this infection are lacking. Therefore, the drug is not recommended during varicella.

The drug should be administered with caution to patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Like other NSAIDs, dexketoprofen trometamol may mask symptoms of infectious diseases during treatment. In isolated cases, activation of soft tissue infections has been reported during NSAID use. Therefore, if signs or symptoms of bacterial infection appear or worsen during treatment, patients are advised to seek immediate medical attention.

One ampoule of the drug contains 200 mg of ethanol, equivalent to 5 mL of beer or 2.08 mL of wine per dose. The drug may have a negative effect on individuals suffering from alcoholism. The ethanol content should be considered when using the drug in pregnant women, breastfeeding women, children, and patients at risk (e.g., those with liver disease or epilepsy). The drug contains less than 1 mmol of sodium (23 mg) per dose and is therefore practically sodium-free.

Use during pregnancy or breastfeeding.

Dexofen is contraindicated during the third trimester of pregnancy and during breastfeeding.

Pregnancy.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis during early pregnancy increases the risk of miscarriage and fetal congenital heart defects and abdominal wall defects. The absolute risk of cardiovascular anomalies increases from <1% to approximately 1.5%. The risk is considered to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors have caused increased pre- and post-implantation losses and increased embryofetal mortality. Additionally, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal developmental abnormalities, including cardiovascular anomalies, was observed. However, animal studies with dexketoprofen did not reveal toxic effects on reproductive organs. From the 20th week of pregnancy, drug use may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after treatment initiation and is usually reversible upon discontinuation. Dexketoprofen may be prescribed during the first and second trimesters of pregnancy only if absolutely necessary. When prescribing dexketoprofen to women planning pregnancy or during the first and second trimesters, the lowest effective dose should be used for the shortest possible duration. Fetal oligohydramnios monitoring should be considered after several days of dexketoprofen exposure starting from the 20th week of pregnancy. Dexketoprofen use should be discontinued if oligohydramnios is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxicity, e.g., premature closure of the ductus arteriosus and pulmonary hypertension;
• renal dysfunction (see above).

Risks to the mother at the end of pregnancy and to the newborn:

• prolonged bleeding time due to inhibition of platelet aggregation, even at low doses;
• inhibition of uterine contractility, leading to prolonged labor and delayed delivery.

Breastfeeding.

There are no data on the passage of dexketoprofen into breast milk. Dexofen is contraindicated during breastfeeding.

Fertility.

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and therefore is not recommended for women planning pregnancy. Women experiencing infertility or undergoing fertility investigations should consider discontinuing the drug.

If dexketoprofen is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the lowest effective dose should be used for the shortest possible duration.

Ability to affect reaction speed when driving or operating machinery.

Dizziness, visual disturbances, or somnolence may occur during treatment with the drug. In such cases, the ability to react quickly, orient in traffic situations, and drive or operate machinery may be impaired.

Method of Administration and Dosage

Adults. The recommended dose is 50 mg every 8–12 hours. If necessary, the next dose may be administered after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use and should be used only during the period of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms. In cases of moderate to severe postoperative pain, the drug may be used as indicated in the same recommended doses in combination with opioid analgesics.

Elderly patients. Dose adjustment is generally not required. However, due to physiological decline in renal function, a lower dose is recommended: the maximum daily dose should be limited to 50 mg in patients with mild renal impairment.

Hepatic impairment. For patients with mild or moderate hepatic impairment (5–9 points on the Child-Pugh scale), the maximum daily dose should be reduced to 50 mg, and liver function should be closely monitored. The drug is contraindicated in patients with severe hepatic disease (10–15 points on the Child-Pugh scale).

Renal impairment. For patients with mild renal impairment (creatinine clearance 60–89 mL/min), the maximum daily dose should be reduced to 50 mg. The drug is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 59 mL/min).

Children and adolescents. The drug should not be used in children and adolescents due to lack of data on efficacy and safety.

Method of Administration

Intramuscular injection

The injection solution should be administered slowly and deeply into the muscle.

Intravenous infusion

For intravenous infusion, the contents of a 2 mL ampoule should be diluted in 30–100 mL of 0.9% sodium chloride solution, glucose solution, or Ringer's lactate solution. The infusion solution should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution must be clear and transparent. The infusion should be administered over 10–30 minutes. Exposure of the prepared solution to natural daylight must be avoided.

The drug, when diluted in 100 mL of 0.9% sodium chloride solution or glucose solution, may be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine, and theophylline.

The drug must not be mixed in the infusion solution with promethazine or pentazocine.

Intravenous injection (bolus administration)

If necessary, the contents of one ampoule (2 mL of injection solution) should be administered intravenously over at least 15 seconds.

The drug may be mixed in small volumes (e.g., in a syringe) with injection solutions of heparin, lidocaine, morphine, and theophylline.

The drug must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine, or hydrocortisone, as a white precipitate may form.

The drug should only be mixed with medicinal products specified above.

When administered intramuscularly or as an intravenous bolus, the drug should be administered immediately after being drawn from the ampoule.

No changes in active ingredient content due to adsorption have been observed during storage of diluted solutions in polyethylene bags or in administration devices made of ethylene-vinyl acetate, cellulose propionate, low-density polyethylene, or polyvinyl chloride.

The drug is intended for single use only; any remaining solution must be discarded. Before administration, ensure that the solution is clear and colorless. The solution must not be used if it contains solid particles.

Children.

The drug should not be used in children and adolescents due to lack of data on efficacy and safety.

Overdose.

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, dizziness, disorientation, headache). In case of accidental overdose, symptomatic treatment appropriate to the patient's condition should be initiated immediately. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse reactions.

The table below lists adverse reactions classified by organ systems and frequency of occurrence, which, according to clinical trial data, are considered at least possible to be related to dexketoprofen trometamol, as well as adverse reactions reported after the drug was marketed.

Gastrointestinal disorders were observed most frequently.

Peptic ulcer, perforation, or gastrointestinal bleeding (sometimes fatal), particularly in elderly patients, may occur. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may develop during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure, which may be associated with the use of NSAIDs, have also been reported. As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which generally occurs in patients with systemic lupus erythematosus or mixed connective tissue disorders, and blood disorders (purpura, aplastic and hemolytic anemia; rarely agranulocytosis and bone marrow hypoplasia). Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), are possible.

According to the results of clinical studies and epidemiological data, the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with a small increased risk of thrombotic events such as myocardial infarction and stroke.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Protect from heat and light. After dilution, the solution should be stored for 24 hours at a temperature of 2 to 8 °C. Keep out of reach of children.

Incompatibilities.

The drug must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, meperidine, or hydrocortisone, as a white precipitate may form.

Diluted infusion solutions prepared as described in the section "Intravenous infusions" must not be mixed with promethazine or pentazocine.

Packaging. 2 ml in an ampoule; 5 ampoules in a plastic blister pack, in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Steril-Jen Life Sciences (P) Ltd.

Manufacturer's address and location of its business activity.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry, 605110, India.